title: α1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-β/activin-mediated signaling.
abstract: It is well known that α1,6-fucosyltransferase (Fut8) and its products, α1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that Fut8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that α1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of α1,6-fucosylation. The knockdown (KD) of Fut8 promoted a significant enhancement of neurite formation and induction of neurofilament expression. Surprisingly, the levels of phospho-Smad2 were greatly increased in the KD cells. Finally, we found that the activin-mediated signal pathway was essential for these changes in KD cells. Exogenous activin, not TGF-β1, induced neurite outgrowth and phospho-Smad2. In addition, the α1,6-fucosylation level on the activin receptors was greatly decreased in KD cells, while the total expression level was unchanged, suggesting that α1,6-fucosylation negatively regulated activin-mediated signaling. Furthermore, inhibition of activin receptor-mediated signaling or restoration of Fut8 expression rescued cell morphology and phospho-Smad2 levels, which were enhanced in KD cells. Considering the fact that α1,6-fucosylation is important for TGF-β-mediated signaling, the results of this study strongly suggest that Fut8 plays a dual role in TGF-β/activin-mediated signaling.
authors.affiliation: 1Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai Miyagi, 981-8558, Japan. jgu@tohoku-pharm.ac.jp.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.forename: Tomoya
authors.initials: T
authors.lastname: Isaji
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D051379:Mice; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D051899:Smad2 Protein; C497784:Smad2 protein, rat; D016212:Transforming Growth Factor beta; D028341:Activins; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase
keywords: N-glycosylation; cell differentiation; glycosyltransferase